Deep brain stimulation (DBS) has emerged rapidly as a treatment for movement disorders and is under investigation for treatment of epilepsy and psychiatric disorders. However, the mechanism(s) of action of DBS are still unclear, and this lack of understanding limits full development and optimization of this promising treatment. Presently, DBS uses regular (constant interpulse interval) high frequency stimulus trains, and the beneficial (lesion-like) effects of DBS are only observed at high (>100 Hz) stimulation frequencies. Although effective, high frequency stimulation generates stronger side-effects than low frequency stimulation, the therapeutic window between the voltage that generates the desired clinical effect(s) and the voltage that generates side effects decreases with increasing frequency, and high stimulation frequencies increase power consumption and shorten implant lifetime, as compared to lower frequencies. We propose to determine the effect of non-regular (variable interpulse interval) stimulation trains on motor function and side effects in persons with Parkinson's disease and on neuronal activity in a computational model of the basal ganglia. We will apply stimulation patterns with variable interpulse intervals expected to create a range of motor effects from exacerbation of symptoms to relief of symptoms, and these data will be used to test the hypothesis that regularization of the output of the stimulated nucleus is required for efficacy of DBS. The results will provide further insight into the mechanisms of action of DBS and guide design of novel stimulation patterns. Subsequently, we will design and test novel, non-regular stimulation patterns that are expected to produce relief of motor symptoms at lower average frequencies than continuous, high rate stimulation. These stimulus trains are expected to increase the efficacy of DBS by reducing the intensity of side effects, increasing the dynamic range between the onset of the desired clinical effect(s) and side effects (and thereby reducing sensitivity to the position of the electrode), and decreasing power consumption. The outcome of this project will be an increased understanding of the mechanisms of action of DBS, and this will facilitate selection of optimal surgical targets as well as treatments for new disorders. The second outcome will be novel pulse patterns that are expected to improve outcomes of DBS by reducing side effects and prolonging battery life. [unreadable] [unreadable] [unreadable]